Diabetes mellitus or diabetes is a chronic metabolic disease that can cause blindness, kidney failure, nerve damage, and confers an increased risk of ischemic heart disease, stroke and peripheral vascular disease. Diabetes is divided into two major categories: type 1 or insulin- dependent diabetes mellitus (IDDM), and type 2 or non-insulin dependent diabetes mellitus (NIDDM). In this country, the incidence of diabetes is approximately 4.5%, of which 90% is type 2 diabetes. In 1992, diabetes care required roughly 14.6% of the total U.S. health care expenditure ($105 billion). Many of these patients also suffer from diabetic complications. Considering the heterogeneity of this disease, and the limitations of current therapies, such as high secondary failure rates and side effects, there is an urgent need to explore new anti- diabetic agents. This research project is related to the development of useful products in the field of complementary and alternative medicine. This proposal will focus on our studies on anti-diabetic effects of Panax ginseng, and this project is a continuation of our previous ginseng pharmacological studies. Recently, in our preliminary studies, we observed exciting results on anti-diabetic actions in ob/ob mice using Panax ginseng berry (or fruit) extract, other than the commonly used root extract. The ob/ob mice is a genetic model for type 2 diabetes, and these animals are extremely insulin resistant and have fasting blood glucose levels that are significantly higher than that of lean mice. Data from our pilot observation showed that extract of Panax ginseng berry normalized hyperglycemia and increased insulin sensitivity in ob/ob mice. In addition, we analyzed the constituents of the ginseng berry by HPLC analysis and found that, compared to ginseng root, the ginseng berry has a distinctive profile of ginsenosides, the vital constituent of ginseng. In this revised proposal, we will test the hypothesis that Panax ginseng berry extract has significant anti-hyperglycemic activity. The project aims to identify the anti-hyperglycemic constituents of Panax ginseng berry, and synergistic effects between these constituents. We will also investigate mechanisms of action of these active component(s). Our strategy is to use an in vivo-guided chemical fractionation method to isolate the pure, biologically active, anti-hyperglycemic compound(s) from Panax ginseng berry using the ob/ob mouse. Improvements in glucose homeostasis, glucose tolerance, and in vivo insulin sensitivity will be tested. The results of the proposed project will also help fill gaps in our knowledge before therapeutic agents can be developed.